Project Summary Multiple sclerosis (MS) is characterized by progressive demyelination of axons in the central nervous system (CNS). One major approach to developing new MS treatments is the development of therapeutics that can act on myelin-producing oligodendrocytes to enhance the production and/or stability of myelin. Toward this end, it is important to identify potential drug targets that are selectively enriched in oligodendrocytes and capable of promoting myelin stability. GPR37 is a nervous system-specific G protein-coupled receptor that is highly expressed in oligodendrocytes. We performed proteomic analyses of brain tissue from GPR37 knockout (Gpr37-/-) mice and found that one of the most dramatically down-regulated proteins was the myelin- associated glycoprotein (MAG), which is a myelin-enriched protein known to regulate myelin stability. In parallel studies, we found that GPR37 and MAG form complexes in cells. Since MAG-deficient mice are known to exhibit significantly more severe demyelination in response to insults, we explored the Gpr37-/- mice in the cuprizone model of demyelination and found that these mice exhibit a much more dramatic loss of myelin than wild-type mice in response to cuprizone treatment. Given the striking similarity in phenotypes between Gpr37-/- and MAG-deficient mice, we hypothesize that the interaction between GPR37 and MAG exerts effects on oligodendrocyte physiology and myelination. This hypothesis will be tested by i) dissecting the structural determinants of the interaction between GPR37 & MAG and ii) studying mutual regulation between GPR37 and MAG in cultured oligodendrocytes from Gpr37-/- mice. These studies will shed light on the interaction and mutual regulation between the oligodendrocyte-enriched proteins GPR37 and MAG, which will lead to a greater understanding of both proteins in the regulation of oligodendrocyte physiology and myelination. Moreover, the studies proposed here will enhance our knowledge of the action of GPR37 in regulating myelination and thereby set the stage for the targeting of this receptor by novel therapeutics aimed at treating MS and other myelination disorders. ! !